Liver cancer: WISP3 suppresses hepatocellular carcinoma progression by negative regulation of β-catenin/TCF/LEF signalling
Liver cancer: WISP3 suppresses hepatocellular carcinoma progression by negative regulation of β-catenin/TCF/LEF signalling
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DOI：
10.1111/cpr.12583
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发表时间：
2019-05-01
影响因子：
8.5
通讯作者：
Xie, Dong
中科院分区：
文献类型：
--
作者：
Gao, Hong;Yin, Fen-Fen;Xie, Dong
目的Wnt 1诱导的信号通路蛋白3（WISP 3/CCN 6）属于CCN（CYR 61/CTGF/NOV）蛋白家族，该家族的异常调节与多种肿瘤的致瘤性有关。在这项研究中，我们需要探索它在肝细胞癌中的作用，而这在很大程度上仍然是难以捉摸的。材料与方法采用qRT-PCR和Western blotting检测WISP 3/CCN 6的表达。MTT法检测WISP 3对肝癌细胞增殖的影响，Boyden小室检测WISP 3对肝癌细胞转移的影响。在裸鼠体内检测WISP 3对肝癌生长和转移能力的影响。免疫荧光和Western blotting证实了相关机制的研究。结果WISP 3在肝癌临床标本和细胞系中表达明显下调，且下调程度与肿瘤大小相关。WISP 3在HCC细胞中的强制表达显著抑制体外细胞生长和迁移以及体内肿瘤生长和转移接种。相反，WISP 3的下调加速细胞增殖和迁移，并促进体内转移。进一步的研究表明，WISP 3通过激活糖原合成酶激酶-3 β（GSK 3 β）抑制β-连环蛋白向细胞核的易位。此外，组成型活性β-连环蛋白阻断了WISP 3对HCC的抑制作用。结论WISP 3通过负调控β-catenin/TCF/LEF信号通路抑制HCC的进展，为WISP 3治疗HCC提供了一个潜在的候选基因。
Objectives Wnt1-inducible signalling pathway protein 3 (WISP3/CCN6) belongs to the CCN (CYR61/CTGF/NOV) family of proteins, dysregulation of this family contributed to the tumorigenicity of various tumours. In this study, we need to explore its role in hepatocellular carcinoma that remains largely elusive. Materials and Methods The expression of WISP3/CCN6 was analysed by qRT-PCR and Western blotting. Effects of WISP3 on proliferation and metastasis of HCC cells were examined, respectively, by MTT assay and Boyden Chamber. Roles of WISP3 on HCC tumour growth and metastatic ability in vivo were detected in nude mice. Related mechanism study was confirmed by immunofluorescence and Western blotting. Results The expression of WISP3 was significantly downregulated in HCC clinical samples and cell lines, and reversely correlated with the tumour size. Forced expression of WISP3 in HCC cells significantly suppressed cell growth and migration in vitro as well as tumour growth and metastatic seeding in vivo. In contrast, downregulation of WISP3 accelerated cell proliferation and migration, and promoted in vivo metastasis. Further study revealed that WISP3 inhibited the translocation of beta-catenin to the nucleus by activating glycogen synthase kinase-3 beta (GSK3 beta). Moreover, constitutively active beta-catenin blocked the suppressive effects of WISP3 on HCC. Conclusions Our study showed that WISP3 suppressed the progression of HCC by negative regulation of beta-catenin/TCF/LEF signalling, providing WISP3 as a potential therapeutic candidate for HCC.